Type 2 diabetes involves reduced ?-cell mass and impaired insulin secretion, but the relationship between mass and secretion is not well understood. Cyclin dependent kinases (Cdks) regulate cell cycle machinery and ?-cell proliferation and could be possible targets for new drugs to increase ?-cell mass in patients. Our new data, however, shows that interrupting Cdk2 signaling unexpectedly disrupts ?-cell function long before changes in ?-cell mass occur, suggesting Cdk2 might be an integrator of ?-cell proliferation and secretory function. We hypothesize that Cdk2 affects ?-cell function by interacting with ion channels, the insulin receptor signaling pathway, and ?-cell fuel metabolism. We will take advantage of a mouse model lacking Cdk2 in its ?-cells and use novel metabolic sensors combined with patch-clamp electrophysiology and insulin secretion assays to (1) determine the targets of Cdk2 in the ?-cell secretory pathway, (2) determine the role of Cdk2 in controlling ?-cell bioenergetics, and (3) establish the Cdk2 pathway in human islets and test whether Cdk2 expression rescues ?-cell function in diabetic human islets. To accomplish these aims, my mentor, Dr. Les Satin, will provide support for the electrophysiology, and my co-mentor Dr. Rane and collaborator Dr. Bernal- Mizrachi will provide training in the use of more advanced diabetes models. The collaborative environment at the Brehm Diabetes Center will provide access to reagents and expertise that will support this work and enable the creation of other mouse models to acutely delete Cdk2. The access to resources and training we propose will allow me to establish an independent line of research and will promote my development, productivity, and independence. In addition, the results obtained will be important for the development of new treatments for increasing ?-cell mass and secretory function in Type 2 diabetics.